Rashmi Bagga

Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans

Hydatidiform mole (HM) is an abnormal human pregnancy with no embryo and cystic degeneration of placental villi. We report five mutations in the maternal gene NALP7 in individuals with familial and recurrent HMs. NALP7 is a member of the CATERPILLER protein family involved in inflammation and apoptosis. NALP7 is the first maternal effect gene identified in humans and is also responsible for recurrent spontaneous abortions, stillbirths and intrauterine growth retardation.

NLRP7 in the spectrum of reproductive wastage: rare non-synonymous variants confer genetic susceptibility to recurrent reproductive wastage

Background NLRP7 mutations are responsible for recurrent molar pregnancies and associated reproductive wastage. To investigate the role of NLRP7 in sporadic moles and other forms of reproductive wastage, the authors sequenced this gene in a cohort of 135 patients with at least one hydatidiform mole or three spontaneous abortions; 115 of these were new patients. Methods/Results All mutations were reviewed and their number, nature and locations correlated with the reproductive outcomes of the patients and histopathology of their products of conception. The presence of NLRP7 mutations was demonstrated in two patients with recurrent spontaneous abortions, and some rare non-synonymous variants (NSVs), present in the general population, were found to be associated with recurrent reproductive wastage. These rare NSVs were shown to be associated with lower secretion of interleukin 1β and tumour necrosis factor and therefore to have functional consequences similar to those seen in cells from patients with NLRP7 mutations. The authors also attempted to elucidate the cause of stillbirths observed in 13% of the patients with NLRP7 mutations by examining available placentas of the stillborn babies and live births from patients with mutations or rare NSVs. A number of severe to mild placental abnormalities were found, all of which are known risk factors for perinatal morbidity. Conclusions The authors recommend close follow-up of patients with NLRP7 mutations and rare NSVs to prevent the death of the rare or reduced number of babies that reach term.

Evaluation of the Pyruvate Kinase isoenzyme tumor (Tu M2-PK) as a tumor marker for cervical carcinoma.

Various isoforms of the glycolytic enzyme pyruvate kinase are expressed in different cell types. One of these isoforms, Tu M2‐PK, is over‐expressed in tumor cells and released into body fluids. Plasma determination of Tu M2‐PK has been shown to discriminate between benign and malignant lesions. Tu M2‐PK was quantitated in the plasma of 50 patients with cervical carcinoma, 10 patients with chronic cervicitis and 10 healthy controls. The concentration of Tu M2‐PK was determined by commercial kits using a sandwich enzyme linked immunosorbent assay based on two monoclonal antibodies (clone I and II) specific for Tu M2‐PK. The sensitivity of the test for discrimination of malignant from non‐malignant condition was 82% with a specificity of 60%. Highly significant statistical difference was found in the means of three groups (P = 0.0002). The present results indicate that Tu M2‐PK can be used as a tumor marker in follow‐up of patients with cervical carcinoma.

Pheochromocytoma associated with pregnancy

Pheochromocytoma associated with pregnancy is rare with potentially lethal consequences. Antepartum diagnosis improves the maternal and perinatal outcome. The issue of mode of delivery is unresolved. Its definitive treatment is surgical resection preceded by medical management. Surgical resection may be done during caesarean section as is reported in the present case.

A Strong Founder Effect for two NLRP7 Mutations in the Indian Population: an Intriguing observation

Hydatidiform mole (HM) is an abnormal human pregnancy characterized by absence of, or abnormal, embryonic development and hydropic degeneration of chorionic villi. The common form of this condition occurs once in every 1000–1500 pregnancies in Western countries (1), but at higher frequencies in India. The incidence of HMs in India is 1 in every 83–500 pregnancies depending on regions and studies (2, 3). HMs are usually sporadic and not recurrent. Among women with sporadic moles, 1–6% will have a second mole (4–11), and 10–20% will have a second non-molar reproductive wastage, mostly as a spontaneous abortion (7, 11, 12). The frequency of familial recurrent HMs (RHMs) is not known, but such cases are believed to be very rare. To date, 23 different mutations in NLRP7 have been reported in women with RHMs and reproductive wastage. Four of these mutations, p.Arg693Pro, p.Glu710Aspfs7X, p.Leu750Val, p.Leu825X, have been found in unrelated families from the same population indicating the presence of founder effects for these mutations (13–16). We previously reported two mutations in Indian families, p.Arg693Pro and p.Asn913Ser, and the former was found in two unrelated families (14). In this study, we searched for mutations in NLRP7 in 10 new unrelated Indian patients with recurrent HMs and reproductive wastage. Eight of the cases originate from various states in Northwest India, Jammu and Kashmir, Punjab, Chandigarh, Haryana, and Uttar Pradesh, and two cases, MoIn105 and MoIn106, originate from West Pakistan and migrated to India about 50 years ago. Mutation analysis was performed as previously described by genomic DNA sequencing of the 11 NLRP7 exons in the two directions and revealed NLRP7 mutations in seven patients. All the seven patients had two previously identified mutations in Indian patients, c.2078G>C, p.Arg693Pro and c.2738A>G, p.Asn913Ser. Three patients were compound heterozygous for the two mutations; three were homozygous for p.Arg693Pro; and one was homozygous for p.Asn913Ser. The analysis of available parents and relatives demonstrated the segregation of the mutations in their respective families (Figure 1). In family MoIn93, a woman with a history of infertility of unexplained clinical origin was found compound heterozygous for the two mutations. To date, we have analyzed 12 unrelated Indian patients, selected based only on their medical history and not on linkage to the locus spanning NLRP7, and found NLRP7 mutations in nine of them (75%). This result was unexpected since only half of patients with recurrent HM and no family history of moles referred to our laboratory (from various populations) have mutations/variants in NLRP7. The DNA change leading to p.Arg693Pro was found on 12 chromosomes (66.6%) and the allele leading to p.Asn913Ser on six chromosomes (33.4%). Haplotypes were established based on alleles found in five homozygous patients and on the analysis of three heterozygous patients and their available parents and siblings at 30 single nucleotide polymorphisms in NLRP7. Haplotype analysis shows a common haplotype carrying each of the mutations and demonstrates the presence of a strong founder effect for these two mutations in the Indian population (Table 1). This is further supported by the fact that four of the analyzed patients are homozygous despite the absence of known consanguinity between their parents. The two mutations modify recognition sites for restriction enzymes and can be easily tested in Indian patients with recurrent HMs and reproductive wastage. A number of synonymous and non-synonymous variants were also found in the patients. c.574A>C, p.Met192Leu was found in a heterozygous state in patient 678 and in 2 out 38 controls of Indo-Pakistani origin. All the other variants are known polymorphisms frequently found in several populations. Figure 1 Pedigree structures and reproductive outcomes of seven Indian families with recurrent reproductive wastage and NLRP7 mutations. The reproductive outcomes are listed by chronological order from left to right. Gestational age is from the last menstrual ... Table 1 Haplotype analysis at all NLRP7 variants found in 8 unrelated Indian patients In family MoIn106, one male with one child and no reproductive problems was found compound heterozygous for the two mutations. This is the third reported male with two NLRP7 mutations and no reproductive problems (13). Our data demonstrate the presence of two founder mutations in the Indian population, expand further the involvement of NLRP7 mutations to a wider spectrum of reproductive wastage, and provide further indications that NLRP7 mutations have no consequences on male reproduction. The presence in several populations of founder effects for a condition that prevents the reproduction of homozygous females is by itself intriguing and may reveal in the future male and/or heterozygous females advantage.

Pre‐induction sonographic assessment of the cervix in the prediction of successful induction of labour in nulliparous women

Objective:  To compare the efficacy of ultrasonographic cervical assessment with Bishop score before induction of labour in predicting the success of labour induction in nulliparous women.

Mechanical valve prosthesis and anticoagulation regimens in pregnancy: a tertiary centre experience

OBJECTIVE This study was undertaken to analyze the maternal and perinatal outcome in women with prosthetic heart valves on different anticoagulant regimens. STUDY DESIGN A retrospective chart review of pregnancies in 40 women with mechanical valve prostheses at a tertiary referral centre from 1997 to 2010. The main outcome measures were major maternal complications and perinatal outcome. RESULTS The valves replaced were mitral (67.5%), aortic (15.0%), or both (17.5%). Forty-nine pregnancies (72.1%) resulted in live births, 3(4.4%) had stillbirths, and 13(19.1%) had spontaneous abortions and 1(1.4%) underwent therapeutic abortions. The live birth rate was higher in women on heparin (78.3%) compared with those on warfarin (66.9%). There were 2 maternal deaths due to acute mitral valvular thrombosis while on acenocoumarol in the second trimester. Hemorrhagic complications occurred in 3 patients on heparin in the postpartum period, 2 of whom required transfusion. In addition one patient who was on acenocoumarol developed secondary hemorrhage. CONCLUSION No anticoagulant regimen can be said to be entirely safe for use during pregnancy as there is a degree of risk with each regimen. Further larger studies are needed to come up with sufficient evidence-based recommendations for the best possible management of such patients to reduce the maternal risks after mechanical heart valve replacement without compromising fetal outcome.

Unsafe abortion: a neglected tragedy. Review from a tertiary care hospital in India.

Aim: With 16% of the worlds population, India accounts for over 20% of the worlds maternal deaths. The maternal mortality ratio, defined as the number of maternal deaths per 100 000 live births is incredibly high at 408 per 100 000 live births for the country. Abortion has been legalized in India for the past three decades. However, the share of unsafe abortion as a cause of maternal mortality continues to be alarming. The objective of the present study is to identify the magnitude of problem of unsafe abortion in India.

Serological screening for antenatal toxoplasma infection in India

PURPOSE Detection of infection caused by Toxoplasma gondii during pregnancy to prevent congenital infection. MATERIALS AND METHODS This study was carried out from January 2005 to 2006 in 300 pregnant women. Antitoxoplasma IgG, IgM, IgA antibody and IgG avidity were assessed using ELISA. At least two samples were taken at least 3 weeks apart preferably one in each trimester. RESULT Of these 300 pregnant women, anti toxoplasma IgG antibodies were detected in 46 (15.33%) cases, while 9 (3%) had positive anti toxoplasma IgM with IgA and /low IgG avidity antibodies suggestive of acute infection during or just before pregnancy. CONCLUSION The results indicate that about 85% of female population of Chandigarh is susceptible to toxoplasma infection and thus should be specifically educated about prevention of this infection during pregnancy.

Antitrichomonas IgG, IgM, IgA, and IgG subclass responses in human intravaginal trichomoniasis

Trichomoniasis, caused by the protozoan parasite Trichomonas vaginalis, is a major nonviral sexually transmitted disease. Clinical spectrum varies from an asymptomatic state to mild, moderate, or severe symptoms. However, the exact factors leading to the variations in symptoms have not been well elucidated. Host’s immune response to the parasite may be playing a role in varied symptomatology. The present study reports antitrichomonas IgM, IgA, IgG and its subclasses in doubling dilutions of serum and diluted vaginal washes of six T. vaginalis-infected symptomatic and four T. vaginalis-infected asymptomatic women and uninfected controls by enzyme-linked immunosorbent assay (ELISA). No significant difference was observed in serum IgG ELISA absorbance values from symptomatic compared to asymptomatic subjects (p > 0.05) while a significant difference (p < 0.05) was noted in serum IgM in all the tested dilutions and IgA up to a dilution of 400. This is the first report of the detection of specific IgG subclass response in T. vaginalis-infected female patients, and quantitative analysis of the antibody responses indicated that the production of local IgG particularly IgG1 in vaginal secretions may be playing a significant role in establishing symptomatic infection. The interesting observation of the present study is that the specific IgM was detected in 2 (33.3%) symptomatic and T. vaginalis-infected patients in ≥800 dilutions and in 1 (16.6%) up to 200 dilutions in serum, while it was not detectable in the vaginal secretions of symptomatic patients or in the serum and vaginal secretions of asymptomatic T. vaginalis-infected patients.